葡聚糖包裹的纳米氟磷灰石示踪骨髓间充质干细胞
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摘要
研究目的：
骨髓间充质干细胞(bone marrow mesenchymal stem cells, BMSCs)作为临床骨组织工程最常用的种子细胞,已被广泛研究,其标记及示踪问题也颇受大家关注,常用的有机染料如CM-DIL和EGFP等存在荧光寿命短,体内不稳定及潜在的细胞致癌性等不足。水热法合成的掺杂镧系元素氟磷灰石(FHA:Tb3+/Eu3+, Tb/Eu-FHA)纳米粒子的粒度均匀,稳定性好,荧光寿命长,细胞亲和力高,和BMSCs共培养后可被BMSCs吞噬,在特定波长光的激发下可发出绿色／红色荧光。本实验采用水热法合成Tb/Eu-FHA,以葡聚糖进行表面修饰后和比格犬BMSCs共培养,观察Tb/Eu-FHA标记BMSCs效果,检测该纳米粒子对BMSCs增殖及分化影响,并将被标记的BMSCs植入动物体内,观察Tb/Eu-FHA在体内的稳定性,为BMSCs的体外及体内研究提供了一种新的标记手段,为进一步研究再生医学与骨组织工程中BMSCs在体内的迁移及转归提供新的思路。研究方法：
1.以硝酸钙(Ca(NO3)2·4H2O)、硝酸铽(Tb(NO3)3·6H2O)、磷酸钠(Na3PO4·12H2O)、氟化钠(NaF)、十八胺(Octadecylamine)、油酸(Oleic acid)、乙醇(Ethanol)以及环已烷(Cyclohexane)为原料,采用水热法合成掺杂镧系元素(铕Eu或铽Tb)的纳米氟磷灰石,离心收集FHA纳米颗粒,加入环已烷与葡聚糖(Dextran)混合溶液中,并加入四氢呋喃(Tetrahyfrofuran),超声波处理后离心收集,得到经葡聚糖表面修饰的掺杂镧系元素纳米氟磷灰石。
2.掺杂镧系元素纳米氟磷灰石的参数检测：X-射线衍射仪检测掺杂镧系元素纳米氟磷灰石的结晶程度及物象组成,红外吸收光谱分析样品中所含的阴离子基团,透射电镜下观察纳米粒子基本形态、颗粒粒径、粒径分布及团聚等情况。倒置荧光显微镜下观察掺杂不同浓度镧系元素的纳米氟磷灰石的荧光特性,荧光分光光度计检测荧光强度。
3.全骨髓培养法从犬骨髓血中分离纯化犬BMSCs (canine bone marrow mesenchymal stem cells, cBMSCs),体外向成骨、成软骨、成脂三系诱导分化,流式细胞仪检测CD29、CD34、CD44和CD45等细胞表面标志物表达。贴壁纯化培养后的cBMSCs CD29和CD44表达为强阳性,而CD34和CD45的表达为阴性。将cBMSCs和不同浓度的葡聚糖表面修饰后的Tb/Eu-FHA纳米颗粒共培养后,检测cBMSCs增殖及分化情况。
4.倒置荧光显微镜及激光共聚焦显微镜下观察共培养后的cBMSCs荧光强度,real-time PCR检测成骨相关因子碱性磷酸酶(alkaline phosphatase, ALP), I型胶原(alpha1chain of type I collagen, COL1α1)以及骨连蛋白(osteonectin, ON)等mRNA的表达变化,ELISA法检测ALP蛋白表达变化。
5.将共培养后的cBMSCs按1×107/ml接种于PCL支架上,孵箱内放置3天,接种后的支架移植入裸鼠体内背部皮下,术后一个月及三个月取材,裸鼠处死,制作快速冰冻切片、HE染色切片,倒置荧光显微镜下观察。
研究结果：
1.水热法合成的纳米荧光氟磷灰结构规则,呈长粒状结构,直径约20nm,平均长度约110-170,微溶于水。
2. Tb-FHA在激发光激发下呈绿色荧光,发射波长为543nm,而Eu-FHA则呈红色荧光,发射波长为617nm, XRD检测呈典型的FHA六角晶体结构。
3.共培养后的cBMSCs在倒置荧光显微镜及激光共聚焦显微镜下可分别呈现绿色(Tb-FHA)或红色(Eu-FHA)荧光。MTS法检测共培养后细胞增殖情况,50ug/ml、100ug/ml和200ug/ml组各组中细胞增殖未受明显影响。
4. Real-time PCR检测cBMSCs与Tb-FHA共培养后14天、21天各组成骨相关因子ALP、COL1α1和ON表达均明显升高,Tb-FHA对成骨诱导液在成骨诱导方向有协同作用,ELSIA法检测ALP蛋白表达结果与PCR一致。
5.植入裸鼠体内后1月、3月快速冰冻切片及HE染色结果,可见绿色荧光,证明了Tb-FHA在体内可长期存在并发出荧光。
结论：
1.水热法合成的Tb/Eu-FHA颗粒均一,具有典型氟磷灰石晶体结构,在掺杂Tb或Eu后分别发出绿色或红色荧光,荧光强度高,在葡聚糖包裹修饰后由疏水性变为亲水性,细胞亲和力提高,适合用来进行生物学试验。
2.全骨髓培养法可以高效的从比格犬骨髓中分离培养出BMSCs,具有向成骨、成软骨和成脂方向分化的潜能,免疫表型符合骨髓间充质干细胞的特征。
3.葡聚糖修饰的Tb/Eu-FHA生物相容性好,细胞亲和力高,可以用来标记BMSCs。
4.标记后的BMSCs向成骨方向分化,且Tb-FHA和传统的成骨诱导液对BMSCs成骨分化具有协同作用,100ug/ml的浓度为最佳浓度。
5.葡聚糖修饰的Tb-FHA可以用来进行体内示踪,Tb-FHA在体内可长期稳定存在。
6.葡聚糖修饰的Tb/Eu-FHA作为BMSCs的标记及示踪剂,价格低廉、制造简单、便于保存、使用方便且性能稳定,在骨组织工程领域中具有良好的应用前景。
Objective:
BMSCs have been demonstrated as an attractive cell source for tissue-engineering applications because of their ability to be easily isolated and expanded from adult bone marrow aspirates and their versatility for pluripotent differentiation into mesenchymal tissues. To date, however, an ideal agent for monitoring and tracking of transplanted BMSCs is still lacking. The organic fluorescent dyes CM-Dil and BrdU are usually used to track cells in vivo, while it is difficult to achieve long-term efficacy. Terbium (Tb)-or europium (Eu)-doped fluorapatite nanorods (Tb/Eu-FHA) were prepared using the hydrothermal method. The surfaces of the Tb/Eu-FHA nanorods were further conjugated with hydrophilic cationic polymers, such as dextran, to enhance hydrophilicity, biocompatibility and cell penetration. Then, the dextran-coated nanorods were cocultured with bone marrow mesenchymal stem cells (BMSCs). A luminescence signal in the cells was detected after12hours with a laser scanning confocal microscope (LSCM). Our current work attempts to provide an excellent fluorescent cell labelling agent for BMSCs in bone tissue engineering.
Methods:
1. Eu3+or Tb3+-doped FHA nanorods were synthesized via the hydrothermal method. Ca(NO3)2·4H2O, Eu(NO3)3or Tb(NO3)3, Na3PO4·12H2O, octadecylamine, oleic acid, ethanol, NaF and Na3PO4were added sequentially and mixed. The obtained Tb/Eu-FHA nanorods doped were collected by centrifugation.
2. The structure, morphology, and luminescence of the products were determined using X-ray diffraction (XRD), field emission scanning electron microscopy (ESEM), transmission electron microscopy (TEM), and photoluminescence spectra (PL). Surfaces of the Tb-FHA nanorods were further conjugated with hydrophilic cationic polymers such as dextran to enhance the hydrophilic, biocompatibility and cell penetrations.
3. Bone marrow aspirates were harvested from anterior superior iliac spine of the beagle dog. The specific cell surface antigen markers of cBMSCs were examined by flow cytometry (FCM). CD29, CD44, CD34and CD45were examined. Biocompatibility evaluation of dextran-coated Tb/Eu-THA nanorods on BMSCs were performed using MTS assay.
4. The cBMSCs and dextran-coated Tb/FHA at a concentration of100μg/mL were cocultured, and fluorescent images of cBMSCs were collected via laser scanning confocal microscope (LSCM). The mRNA levels of ALP, COLlal, and ON were analysed via real-time PCR assay on days14and21of differentiation. The ALP activity was detected by ELISA on day14and day21of differentiation.
5. The labelled BMSCs were seeded on sterilized PCL scaffold in a concentration of1x107cells/ml, and then implanted subcutaneously into nude mice. Samples were harvested after1and3months of incubation. Specimens were used to make rapid frozen sections that were then stained with haematoxylin and eosin (HE). Images were collected via inverted fluorescence microscope.
Result:
1. Typical FHA nanorods doped with Tb3+are straight nanorods with a diameter of about20nm and lengths ranging from110to170nm. The nanorods possessed uniform morphology and good crystallinity, and hard to soluble in water.
2. Tb-FHA nanorods become luminescent with a maximum emission intensity at543nm (5D4-7F5), and the emission intensity of Eu-FHA nanorods is617nm (5D0-7F2). The result of XRD shows all diffraction peaks can be indexed as typical hexagonal FHA.
3. The green/red fluorescence of cBMSCs can be clearly seen in confocal images with an excitation wavelength of405nm and488nm. No obvious cytotoxicity of Tb-FHA group was observed of the MTS assay. The fluorapatite nanorods act synergistically with the biochemical reagents in osteogenic medium to promote osteogenic differentiation.
4. The mRNA levels of ALP, COLlal, and ON mRNA detected on day14and day21are all up-regulated. Consistent with real-time PCR result, ELSIA assay also shows an increase of ALP protein level.
5. Samples were harvested after1and3months of incubation. Fluorescent images of the rapidly frozen sections were gathered via inverted fluorescence microscope and tipical green fluorescence are shown.
Conclusions:
1. The fluoride substituted hydroxyapatite nanorods doped with lanthanides synthesized using hydrothermal method possess excellent luminescent properties, uniform morphology, good crystallinity, and the uniformity of sizes. The luminescence shows high photostability, high resistance to photobleaching, and long luminescent lifetime.
2. BMSCs can be efficient isolat from the bone marrow of beagle dogs suing whole bone marrow culture method. The cBMSCs show the potential of osteogenic, adipogenic and chondrogenic differentiation. Immunephenotype matches bone marrow mesenchymal stem cell characteristics.
3. Dextran-coated Tb/Eu-FHA nanorods proved to be successful in labelling cBMSCs. The nanorods possess excellent biocompatibility, concentration of100μg/mL is recommended, high concentration is useless.
4. Dextran-coated Tb/Eu-FHA nanorods promote osteogenic differentiation of cBMSCs. There is a synergistic effect between the fluorapatite nanorods and biochemical reagents in osteogenic medium on osteogenic differentiation.
5. Dextran-coated Tb/Eu-FHA nanorods can be used as an in vivo tracer, the fluorescence can persist for a long time in vivo.
6. Lower costs, improved performance, simplicity of manufacture, facilitation of use and storage make the nanorods an make the nanorods may become excellent fluorescent cell labelling agent for BMSCs in bone tissue engineering.
骨髓间充质干细胞(bone marrow mesenchymal stem cells, BMSCs)作为临床骨组织工程最常用的种子细胞,已被广泛研究,其标记及示踪问题也颇受大家关注,常用的有机染料如CM-DIL和EGFP等存在荧光寿命短,体内不稳定及潜在的细胞致癌性等不足。水热法合成的掺杂镧系元素氟磷灰石(FHA:Tb3+/Eu3+, Tb/Eu-FHA)纳米粒子的粒度均匀,稳定性好,荧光寿命长,细胞亲和力高,和BMSCs共培养后可被BMSCs吞噬,在特定波长光的激发下可发出绿色／红色荧光。本实验采用水热法合成Tb/Eu-FHA,以葡聚糖进行表面修饰后和比格犬BMSCs共培养,观察Tb/Eu-FHA标记BMSCs效果,检测该纳米粒子对BMSCs增殖及分化影响,并将被标记的BMSCs植入动物体内,观察Tb/Eu-FHA在体内的稳定性,为BMSCs的体外及体内研究提供了一种新的标记手段,为进一步研究再生医学与骨组织工程中BMSCs在体内的迁移及转归提供新的思路。研究方法：
1.以硝酸钙(Ca(NO3)2·4H2O)、硝酸铽(Tb(NO3)3·6H2O)、磷酸钠(Na3PO4·12H2O)、氟化钠(NaF)、十八胺(Octadecylamine)、油酸(Oleic acid)、乙醇(Ethanol)以及环已烷(Cyclohexane)为原料,采用水热法合成掺杂镧系元素(铕Eu或铽Tb)的纳米氟磷灰石,离心收集FHA纳米颗粒,加入环已烷与葡聚糖(Dextran)混合溶液中,并加入四氢呋喃(Tetrahyfrofuran),超声波处理后离心收集,得到经葡聚糖表面修饰的掺杂镧系元素纳米氟磷灰石。
2.掺杂镧系元素纳米氟磷灰石的参数检测：X-射线衍射仪检测掺杂镧系元素纳米氟磷灰石的结晶程度及物象组成,红外吸收光谱分析样品中所含的阴离子基团,透射电镜下观察纳米粒子基本形态、颗粒粒径、粒径分布及团聚等情况。倒置荧光显微镜下观察掺杂不同浓度镧系元素的纳米氟磷灰石的荧光特性,荧光分光光度计检测荧光强度。
3.全骨髓培养法从犬骨髓血中分离纯化犬BMSCs (canine bone marrow mesenchymal stem cells, cBMSCs),体外向成骨、成软骨、成脂三系诱导分化,流式细胞仪检测CD29、CD34、CD44和CD45等细胞表面标志物表达。贴壁纯化培养后的cBMSCs CD29和CD44表达为强阳性,而CD34和CD45的表达为阴性。将cBMSCs和不同浓度的葡聚糖表面修饰后的Tb/Eu-FHA纳米颗粒共培养后,检测cBMSCs增殖及分化情况。
4.倒置荧光显微镜及激光共聚焦显微镜下观察共培养后的cBMSCs荧光强度,real-time PCR检测成骨相关因子碱性磷酸酶(alkaline phosphatase, ALP), I型胶原(alpha1chain of type I collagen, COL1α1)以及骨连蛋白(osteonectin, ON)等mRNA的表达变化,ELISA法检测ALP蛋白表达变化。
5.将共培养后的cBMSCs按1×107/ml接种于PCL支架上,孵箱内放置3天,接种后的支架移植入裸鼠体内背部皮下,术后一个月及三个月取材,裸鼠处死,制作快速冰冻切片、HE染色切片,倒置荧光显微镜下观察。
研究结果：
1.水热法合成的纳米荧光氟磷灰结构规则,呈长粒状结构,直径约20nm,平均长度约110-170,微溶于水。
2. Tb-FHA在激发光激发下呈绿色荧光,发射波长为543nm,而Eu-FHA则呈红色荧光,发射波长为617nm, XRD检测呈典型的FHA六角晶体结构。
3.共培养后的cBMSCs在倒置荧光显微镜及激光共聚焦显微镜下可分别呈现绿色(Tb-FHA)或红色(Eu-FHA)荧光。MTS法检测共培养后细胞增殖情况,50ug/ml、100ug/ml和200ug/ml组各组中细胞增殖未受明显影响。
4. Real-time PCR检测cBMSCs与Tb-FHA共培养后14天、21天各组成骨相关因子ALP、COL1α1和ON表达均明显升高,Tb-FHA对成骨诱导液在成骨诱导方向有协同作用,ELSIA法检测ALP蛋白表达结果与PCR一致。
5.植入裸鼠体内后1月、3月快速冰冻切片及HE染色结果,可见绿色荧光,证明了Tb-FHA在体内可长期存在并发出荧光。
结论：
1.水热法合成的Tb/Eu-FHA颗粒均一,具有典型氟磷灰石晶体结构,在掺杂Tb或Eu后分别发出绿色或红色荧光,荧光强度高,在葡聚糖包裹修饰后由疏水性变为亲水性,细胞亲和力提高,适合用来进行生物学试验。
2.全骨髓培养法可以高效的从比格犬骨髓中分离培养出BMSCs,具有向成骨、成软骨和成脂方向分化的潜能,免疫表型符合骨髓间充质干细胞的特征。
3.葡聚糖修饰的Tb/Eu-FHA生物相容性好,细胞亲和力高,可以用来标记BMSCs。
4.标记后的BMSCs向成骨方向分化,且Tb-FHA和传统的成骨诱导液对BMSCs成骨分化具有协同作用,100ug/ml的浓度为最佳浓度。
5.葡聚糖修饰的Tb-FHA可以用来进行体内示踪,Tb-FHA在体内可长期稳定存在。
6.葡聚糖修饰的Tb/Eu-FHA作为BMSCs的标记及示踪剂,价格低廉、制造简单、便于保存、使用方便且性能稳定,在骨组织工程领域中具有良好的应用前景。
Objective:
BMSCs have been demonstrated as an attractive cell source for tissue-engineering applications because of their ability to be easily isolated and expanded from adult bone marrow aspirates and their versatility for pluripotent differentiation into mesenchymal tissues. To date, however, an ideal agent for monitoring and tracking of transplanted BMSCs is still lacking. The organic fluorescent dyes CM-Dil and BrdU are usually used to track cells in vivo, while it is difficult to achieve long-term efficacy. Terbium (Tb)-or europium (Eu)-doped fluorapatite nanorods (Tb/Eu-FHA) were prepared using the hydrothermal method. The surfaces of the Tb/Eu-FHA nanorods were further conjugated with hydrophilic cationic polymers, such as dextran, to enhance hydrophilicity, biocompatibility and cell penetration. Then, the dextran-coated nanorods were cocultured with bone marrow mesenchymal stem cells (BMSCs). A luminescence signal in the cells was detected after12hours with a laser scanning confocal microscope (LSCM). Our current work attempts to provide an excellent fluorescent cell labelling agent for BMSCs in bone tissue engineering.
Methods:
1. Eu3+or Tb3+-doped FHA nanorods were synthesized via the hydrothermal method. Ca(NO3)2·4H2O, Eu(NO3)3or Tb(NO3)3, Na3PO4·12H2O, octadecylamine, oleic acid, ethanol, NaF and Na3PO4were added sequentially and mixed. The obtained Tb/Eu-FHA nanorods doped were collected by centrifugation.
2. The structure, morphology, and luminescence of the products were determined using X-ray diffraction (XRD), field emission scanning electron microscopy (ESEM), transmission electron microscopy (TEM), and photoluminescence spectra (PL). Surfaces of the Tb-FHA nanorods were further conjugated with hydrophilic cationic polymers such as dextran to enhance the hydrophilic, biocompatibility and cell penetrations.
3. Bone marrow aspirates were harvested from anterior superior iliac spine of the beagle dog. The specific cell surface antigen markers of cBMSCs were examined by flow cytometry (FCM). CD29, CD44, CD34and CD45were examined. Biocompatibility evaluation of dextran-coated Tb/Eu-THA nanorods on BMSCs were performed using MTS assay.
4. The cBMSCs and dextran-coated Tb/FHA at a concentration of100μg/mL were cocultured, and fluorescent images of cBMSCs were collected via laser scanning confocal microscope (LSCM). The mRNA levels of ALP, COLlal, and ON were analysed via real-time PCR assay on days14and21of differentiation. The ALP activity was detected by ELISA on day14and day21of differentiation.
5. The labelled BMSCs were seeded on sterilized PCL scaffold in a concentration of1x107cells/ml, and then implanted subcutaneously into nude mice. Samples were harvested after1and3months of incubation. Specimens were used to make rapid frozen sections that were then stained with haematoxylin and eosin (HE). Images were collected via inverted fluorescence microscope.
Result:
1. Typical FHA nanorods doped with Tb3+are straight nanorods with a diameter of about20nm and lengths ranging from110to170nm. The nanorods possessed uniform morphology and good crystallinity, and hard to soluble in water.
2. Tb-FHA nanorods become luminescent with a maximum emission intensity at543nm (5D4-7F5), and the emission intensity of Eu-FHA nanorods is617nm (5D0-7F2). The result of XRD shows all diffraction peaks can be indexed as typical hexagonal FHA.
3. The green/red fluorescence of cBMSCs can be clearly seen in confocal images with an excitation wavelength of405nm and488nm. No obvious cytotoxicity of Tb-FHA group was observed of the MTS assay. The fluorapatite nanorods act synergistically with the biochemical reagents in osteogenic medium to promote osteogenic differentiation.
4. The mRNA levels of ALP, COLlal, and ON mRNA detected on day14and day21are all up-regulated. Consistent with real-time PCR result, ELSIA assay also shows an increase of ALP protein level.
5. Samples were harvested after1and3months of incubation. Fluorescent images of the rapidly frozen sections were gathered via inverted fluorescence microscope and tipical green fluorescence are shown.
Conclusions:
1. The fluoride substituted hydroxyapatite nanorods doped with lanthanides synthesized using hydrothermal method possess excellent luminescent properties, uniform morphology, good crystallinity, and the uniformity of sizes. The luminescence shows high photostability, high resistance to photobleaching, and long luminescent lifetime.
2. BMSCs can be efficient isolat from the bone marrow of beagle dogs suing whole bone marrow culture method. The cBMSCs show the potential of osteogenic, adipogenic and chondrogenic differentiation. Immunephenotype matches bone marrow mesenchymal stem cell characteristics.
3. Dextran-coated Tb/Eu-FHA nanorods proved to be successful in labelling cBMSCs. The nanorods possess excellent biocompatibility, concentration of100μg/mL is recommended, high concentration is useless.
4. Dextran-coated Tb/Eu-FHA nanorods promote osteogenic differentiation of cBMSCs. There is a synergistic effect between the fluorapatite nanorods and biochemical reagents in osteogenic medium on osteogenic differentiation.
5. Dextran-coated Tb/Eu-FHA nanorods can be used as an in vivo tracer, the fluorescence can persist for a long time in vivo.
6. Lower costs, improved performance, simplicity of manufacture, facilitation of use and storage make the nanorods an make the nanorods may become excellent fluorescent cell labelling agent for BMSCs in bone tissue engineering.
引文
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